The goal of this project is to explore the interaction of cocaine and cocaine-like compounds with their binding sites in brain. The binding site or "receptor" thought important for the reinforcing effects of cocaine, at least in animals, is the dopamine transporter. Other effects of cocaine and its congeners are likely to be due to interaction at other sites such as other transporters. Besides developing an understanding of the interaction of cocaine with transporters, this study also reveals potent reversible and irreversible binding ligands for in vitro and in vivo studies of transporter proteins. Some compounds may be useful as treatment medications as well. Several classes of cocaine analogs were tested in binding and uptake studies at the dopamine transporter, and sometimes also at the norepinephrine and serotonin transporters. These studies were carried out using rat brain tissue although sometime human brain tissue was utilized as well. The methods employed were standard radiolabeled ligand binding techniques. Cocaine has a carbomethoxy group in the C-2 position which is required for its activity. Since oxadiazoles are excellent bioisosteres of ester groups, several oxadiazoles were synthesized and tested in binding assays. In general, these compounds showed potencies for the dopamine transporter similar to the parent esters. The most potent analog had an IC-50 of 1.6 nM, and selectivity for the dopamine transporter was high as well. These compounds may have utility as medications to treat drug abuse since replacement of the ester with the oxadiazole will produce a compound that is resistant to metabolism and long-lasting. By producing a series of compounds without the methyl group attached to the nitrogen in the ring structure, we found that demethylation enhanced affinity for the serotonin and norepinephrine transporters between 2- and 44-fold. This will be very useful when trying to design cocaine analogs selective for serotonin and norepinephrine transporters. A series of amides in the C-2 position were synthesized and tested as well. The results indicated the tertiary amides are more potent at the dopamine transporter than primary and secondary amides. Some of the compounds were both potent and highly selective for the dopamine transporter. A QSAR and CoMFA study extended knowledge from the structure-activity work and elucidated some features of the cocaine pharmacophore and provided useful predictive information. Additional compounds will be synthesized using this information.